Melphalan is chemically known as 4-[bis(chloroethyl)amino]phenylalanine and also by other names like L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin. It is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent which is active against selective human neoplastic diseases.
Melphalan is marketed as its hydrochloride salt under the brand name ALKERAN. The synthesis of Melphalan was first disclosed in U.S. Pat. No. 3,032,584 and U.S. Pat. No. 3,032,585.
The following patents and applications describe the synthesis of Melphalan hydrochloride. U.S. Pat. No. 3,032,584 and U.S. Pat. No. 3,032,585 describe process for the production of melphalan free base by protecting glycinic amino group (P-nitro-L-phenyl alanine) with phthalimide functional group followed by esterification to produce ester compound of P-nitro-N-phthaloyl-L-phenyl alanine. Ester derivative of P-nitro-N-phthaloyl-L-phenyl alanine is then subjected to catalytic hydrogenation to reduce nitro group to an amino group, treating the amino compound with ethylene oxide to affect the bishydroxyethylation. The product is then subjected to chlorination followed by hydrolysis and deprotection of the phthaloyl group to produce L-4-[bis(2-chloroethyl)-amino]-phenylalanine.
European patent EP0233733 discloses the process for making L-4-[bis(2-chloroethyl)-amino]-phenylalanine by using phthalimide group to protect glycinic amino group of 4-nitro phenylalanine ethyl ester.
These patents do not disclose a method for isolating the acid addition salts of the L-form of 4-[bis(2-chloroethyl)-amino]-phenylalanine, specifically the hydrochloride salt.
U.S. Pat. No. 4,997,651 discloses a method for preparing melphalan hydrochloride comprising addition of hydrochloric acid to slurry of melphalan free base in an alcohol, preferably ethanol and refluxing the mixture for minimum duration to reduce the level of impurities. Using an alcohol solvent for preparation of the hydrochloride salt results in the formation of the corresponding ester and removal of which could result in lower yield and is tedious process. Complete conversion of free base to hydrochloride salt in a short time on large scale is difficult with alcohol solvents. And the purity reported by HPLC was 97.5%.
RO 57195 describes a method for purification of melphalan free base through formation of the hydrochloride salt followed by treatment with a suitable base such as sodium bicarbonate or sodium acetate.
US2009/240074 A1 describes the synthesis of optically pure 4-(bis-(2-hydroxyethyl)amino)-L-phenylalanine by hydroxyethylation, in a regioselective manner, of the aromatic amino group in presence of a free glycinic amino group. 4-(Bis-(2-hydroxyethyl)amino)-L-phenylalanine was converted to melphalan in presence of POCl3 and when isolated as a sulfate salt a purity of 96% was obtained. Isolation of Melphalan freebase from concentrated HCl reaction mass required distillation of HCl followed by pH adjustment.
Melphalan crudes obtained were converted into hydrochloride salt in water followed by in situ conversion of the hydrochloride salt to free base by pH adjustment. The purity of the free base obtained was 99%. The process required tedious workup to obtain Melphalan.
US 20120116117 describes a process for the preparation of Melphalan HCl, comprising treatment of 4-[bis(2-chloroethyl)-amino]-L-phenylalanine in conc. hydrochloric acid and isolating the obtained 4-[bis(2-chloroethyl)-amino]-L-phenylalanine hydrochloride by azeotropic distillation of the water in presence of toluene and isolation of the product with isopropyl alcohol to obtain the Melphalan HCl with a purity of >99.0% It is clearly evident from the above prior art that the product obtained by known methods generate associated impurities and require extensive purifications. Therefore, to overcome the problems associated with prior art, there is a need to develop an efficient and cost effective method for the synthesis of Melphalan hydrochloride and which can be easily converted to the free base in its pure form.